Archive for the ‘FDA’ Category

I was glancing through The Wall Street Journal. this morning (that period is intentional as I found out recently in their 150th anniversary issue) and saw an article about smallpox, that old enemy of mankind. The CDC issued a media statement saying six vials labeled with the technical name of the disease, variola, had been found in an old storage room belonging to an FDA lab that is on the NIH Bethesda, Maryland facility. Forty-two years ago the FDA took over that lab, among others, and only now were those labs being moved to the main FDA location in the DC area. The vials themselves date back ~60 years and now will be tested to see if the material in them is viable (i.e., live smallpox viruses).

I reviewed the CDC's Bio-hazard Safety Levels; they range from 1 to 4 with more serious infectious agents occupying the higher levels. A BSL-3 agent can cause serious or deadly disease, but either doesn't spread from person to person (at least not easily) and/or has a preventive or treatment known. Plague, rabies virus and West Nile fit into this category. Smallpox is obviously a BSL-4 bug, the most dangerous kind and in the company of Ebola virus. A February 15, 2012 Reuters article, "How secure are labs handling the world's deadliest pathogens?" talked about the precautions used in such a lab in Galveston, Texas. The boss there got entry by swiping a key card, was scanned by 100+ closed-circuit cameras as he opened seven additional locked doors before he reached the lab where another card swipe and a fingerprint scan were necessary for entry. The Washington Post article on the recently found vials has a six-minute video on BSL-4 procedures with a comment that there are three over-lapping types of safety precautions: those for containment of the hazardous material; those for personal protection and overall administrative factors.

And this may get you into BSL-3

The air flow and exhaust systems used in Galveston, the full-body suits with their own air supply and the intruder drills that are conducted all made me somewhat more comfortable. But that's in a government-funded laboratory. Even in the United States, a private-funded lab may not be subject to the same rules and regulations, Elsewhere the procedures that must be followed vary. In 2011 there were 24 known BSL-4 labs in the world with six in the U.S. (The GAO said we had considerably more.) In 2013 there was considerable protest in Boston over the proposed BSL-3 and BSL-4 lab there.

We don't see these anymore.

I've written about smallpox before, but a brief history, available online on a dermatology website was worth reviewing. The disease likely originated in Africa about 12,000 years ago. caused a major epidemic during an Egyptian-Hittite war in 1,350 B.C.E and left typical scars on the mummy of Pharaoh Ramses V who died in 1157 B.C.E. It got to Europe somewhere between the 5th and 7th centuries C.E.; millions died in Europe and the Western Hemisphere before Edward Jenner developed vaccination in 1796. The term came from the Latin word for cow (vaca), as Jenner used fluid from a cowpox-infected dairymaid's hand to inoculate an eight-year-old boy. In 1967 WHO estimated there were 15 million cases of smallpox and 2 million deaths from the disease. Total smallpox deaths over the past 12,000 years have been estimated at 300-500 million, more than all the world wars combined.

By 1980 the World Health Organization declared the globe smallpox-free. In this country, we quit vaccinating the general population in 1972 and stopped giving the inoculation to new military personnel in 1990.

My wife's old shot record shows she got her first vaccination against small pox in 1956 and the last booster in 1980. We were both assigned to bases in the Far East in the early and mid 80s. I can't find my military vaccination record from that time frame, but logically wouldn't have had a booster after 1986 when I got back to a base in Texas. Since immunity is unlikely to last more than ten years, at this stage we'd both be vulnerable to smallpox, like most everyone else.

The only known supplies of the virus remained in government laboratories in the United States and Russia. There has been considerable international protest against keeping those specimens alive starting in the early 1990s, but thus far neither country wants to give in to that pressure. One rationale was the genetic structure of the virus was known, so it could conceivably be recreated by terrorists.

In 2004 the CDC said they had stockpiled enough smallpox vaccine on hand to vaccinate everyone in the United States. I haven't found any updates on that statement. But the U.S. military was still giving those shots to personnel going to USCENTCOM areas (the Middle East and the "stans") until the middle of May, 2014, to Korea for another two weeks and to some special mission troops after that with an end date unspecified.

So now it's the middle of 2014 and, in one manner or another, smallpox is still lingering, fortunately not as an active disease. The CDC is testing those re-found vials of the virus and we'll hear in a couple of weeks is they were still viable.

Having written recently about China's food problems, I knew there were some remaining in the Untied States, but their scope amazed me. Each year forty-eight million of us suffer from food poisoning. Over 125,000 of that group are ill enough to be hospitalized and 3,000 die.

Having seen those numbers on a government website, I decided to review the modern timeline of food-related illness in America and how our laws help prevent it.

One step in meat processing

My initial thought was of Upton Sinclair's 1906 novel, The Jungle, a powerful expose' of the American meat-packing industry. After its publication, public outcry led President Theodore Roosevelt to appoint a special commission to verify Sinclair's tale of the horrors of meat production in Chicago and elsewhere, and eventually led to the meat Inspection Act of 1906 and the Pure Food and Drug Act.

For many years a so-called "Poke and Sniff" system prevailed. The 1907 law said federal employees could inspect and approve (or disapprove) any animal carcasses which were to be sold across state lines. The inspectors could physically monitor the slaughter line, touching and smelling the animals and cuts of meat. They could remove any meat that was rotten, damaged or had abrasions or growths. Some felt that provided only minimal protection for the public, but that's what we had for over eighty years.

I grew up in Wisconsin in the 40s and 50s. My father, in addition to his medical practice, was the local Public Health Officer and I remember going to inspect local area dairy herds with his sanitarian when I was a teenager. I don't recall major food safety issues surfacing in those decades., although there may have been some isolated cases that I didn't pay attention to.

I was in medical school from 1962 to 1966. During that time, two women died in Michigan from botulism, a rare but extremely serious paralytic disease caused by a toxin produced by a bacteria. In their case the toxin was in canned tuna fish. There were other botulism outbreaks in 1971, 1977, 1978 and 1983 with 59 people being affected in the largest such episode. All were related to food being improperly canned or prepared.

In 1985 a huge outbreak of another form of food poisoning happened. This one involved at least 16,284 people (and perhaps up to 200,000) in six different states and was caused by bacterial contamination of milk.

Some new laws only applied to a few food items.

The Department of Agriculture's food safety and inspection timeline appears to skip over a considerable period of time, although a number of laws were passed to strengthen federal regulation of the food chain. The 1957 Poultry Products Inspection Act and the 1970 Egg Products Inspection Act added to the government's ability to prevent food-related illness in specific areas, but wouldn't have prevented the major food-related episodes I just mentioned.

Then in late 1992 and early 1993 an E. coli outbreak sickened 623 and killed 4 children in four western states (Washington, Idaho, Nevada and California). It was eventually traced to contamination of under-cooked Jack in the Box hamburgers with that common bowel bacterium. Those affected developed bloody diarrhea and, in a few cases, severe kidney disease from an entity termed hemolytic-uremic syndrome (HUS). This is a disease which is the most common cause of acute kidney failure in children and usually occurs when an infection in the digestive system produces toxic substances that destroy red blood cells, causing severe kidney injury. The CDC traced the meat back to five slaughter plants in the United States and one in Canada.

In 1998 the USDA introduced a brand-new method for inspecting meat. The "Hazard Analysis and Critical Control Point (HACCP) system had been pioneered by NASA. That agency had protected our astronauts by adopting a system of critical control points, anywhere a germ, invisible to the naked eye, could find its way into a food meant for a space mission.

Pinging off the NASA approach, the USDA also mandated inspectors could order meat plants to do microbial testing. The meat industry became responsible for establishing and submitting their own HACCP plans. Then USDA would review the plan, approve it if it seemed appropriate and inspectors could monitor the plans' compliance with their own safety plans. The problem is the age-old one of the fox guarding the hen-house; inspectors no longer had the power to physically examine the meat on the line. The acronym HACCP was often derided as "Have a cup of coffee and pray."

On January 10th, 2014 two articles were published that changed my mind: the first, in UPI.com's website simply said, "U.S. food Safety a big issue in 2014." It mentioned that already in 2014 the U.S. Department of Agriculture had shut down a meat-processing facility in the state of Minnesota.

The other online article was written by Dr. Margaret A. Hamburg, the Commissioner of Food and Drugs, i.e., the head of the FDA. It discusses the Food Safety Modernization Act (FSMA), signed by President Obama in early January, 2011. It was a reaction to the figures I mentioned at the start of this article.

This law gave the FDA "a legislative mandate to require comprehensive, science-based preventive controls across the food supply."

But let's look at its provisions, some of which make eminent sense and others, in my opinion, ask for the impossible.

On the one hand the FSMA required food facilities to have a written preventive control plan. I agree with that idea, but note it's a complex process with multiple steps involved. Such a plan includes evaluation of possible hazards, figuring out what one has to do to marked alleviate or totally eliminate them, noting how you will monitor these control measures (and keep appropriate records) and specifying what you will do when issues arise. Oh, and by the way, you had a year and a half to do all that.

Other parts of the FSMA involved standards for safely producing and harvesting vegetables and fruits plus another set involving the prevention of "intentional contamination" of food. The latter may be quite difficult. As the law is written, 600 such foreign food facilities must be inspected in its first year with the number doubling for each of five additional years. let's see, that's 600, 1,200, 2,400, 4,800, 9,600 and 19,200. Where in the world would the FDA get enough trained inspectors? And that's assuming that the foreign countries would allow such detailed examinations of their food-producing and exporting businesses.

One of every six Americans becomes ill from food-bourne disease each year. Only a small fraction of them (approximately 1/4th of 1%) need to be hospitalized and even of those who do only 2.3% die. But another way of looking at those mortality statistics is to say it's equivalent to almost 10% of the number who die from motor vehicle accidents each year in this country.

Yesterday's edition of The New York Times had an article by an experienced academic physician that called for a new Lyme disease vaccine, Dr. Stanley A. Plotkin, a professor of pediatrics at the University of Pennsylvania said new CDC data had been released showing a ten-fold greater incidence of the disease than was previously thought. He explored the history of the vaccine put on the market in 1998 by a major US pharmaceutical company, then called SmithKlineBeecham (now it's become GlaxoSmithKline).

I looked for that news release from the CDC and found their old numbers in an August, 2013 online site (30,000 cases a year reported by state and DC health departments) had been superseded by new preliminary figures coming from three different databases. So instead of the numbers we've thought represented human cases, 96% of which occur in thirteen states in the Northeast and upper Midwest, we have 300,000 cases a year, still heavily concentrated in those regions.

The white-footed mouse is the main reservoir for Lyme disease.

In 2011 Richard Ostfeld, a senior disease ecologist working at the Cary Institute in New York published an excellent book, Lyme Disease: The Ecology of a Complex System, aimed at a mixed readership of scientists and nonscientists. I've mentioned this before but should reiterate his finding that white-footed mice were a highly significant reservoir (host animal) for the bacteria that is then transmitted to humans by, in this country, one particular insect-like species, the black-legged tick.It's actually an arachnid, cousin to spiders and scorpions. There are other host species and a variety of predators, weather/climate conditions and habitat factors also play a role.

His work predicted a surge in cases of Lyme disease in the spring of 2012, based on an acorn crop boom-and-bust cycle. The town of Whitman, MA, published an online summary of this prediction quoting the Cary Institute's press release. In brief that mouse species' population soars in a year with an abundant acorn crop and falls markedly when acorns are scarce. The organism that causes Lyme disease is a bacterial species called Borrelia burgdoferi, The white-footed mouse is a superb host for that bug; the mouse doesn't get sick; the bacteria multiplies and there is an abundant supply of B. burgdorferi waiting to spread to other animals. Those mice are also frequently bitten by the tick in question, especially around their ears.

In the seasons of acorn abundance the mouse population soars and the ticks, which need a blood meal three times in their life span (once in the larval storage, once as a nymph and once as an adult), have plenty of mice to feed on.

But then comes a lean crop year for the acorns and the B. burgdorferi infected ticks have to find other blood sources for their next meal. Any mammal will do, but humans are certainly among those available. If we are camping or hiking through an area where the tiny tick nymphs or abound, we may never notice the bite. We may not even be wearing any bug spray or perhaps have more skin exposed than is safest. The nymphs are cold-blooded, so the countryside has to warm up from Winter's blasts before they are ready to feed. If it's a milder cold season (and with global warming that may be the case), the nymphs may be out looking for a meal as early as April.

Forest ecologists from the Cary Institute noted 2010's crop of acorns was very heavy; mouse population numbers rose appropriately. Then, in the fall of 2011, their research site had a marked acorn scarcity. Mouse numbers plummeted leading to a prediction from the group of at least 20% more human cases of Lyme disease.

Let's return to Dr. Plotkin's article in the New York Times. Eight years ago he almost lost an adult son to a cardiac complication of a Lyme infection. Alec D. Plotkin was walking his dog on an August day in Pennsylvania when he abruptly lost consciousness and collapsed. In 2011 his father (Dr. Plotkin) published an article, "Correcting a Public health Fiasco: The Need for a New Vaccine against Lyme Disease," in the Journal Clinical Infectious Diseases. At that time the yearly US case estimate was (reported cases only) roughly 20,000, but as Dr. Plotkin noted, "the extent of underreporting is unknown." He mentioned that the state of Connecticut's statistics would imply that 1% of its entire population could develop the ailment over a ten-year stretch and that nine of sixteen countries in Europe, where Lyme disease is caused by a different variant of B. burgdorferi, had data showing an increased case incidence over time.

But you may or may not have the pathognomonic rash.

On Septmeber 19, The New York Times published the obit of Dr. Stephen E. Malawista, who, as chief of rheumatology at Yale School of Medicine had, with his postdoctoral student, Allen C. Steere, defined Lyme disease. In the fall of 1975 two women from Lyme, CT and Old Lyme had developed joint swelling, peculiar rashes and neurological complaints undiagnosable by their local physicians. Each went to Yale seeking answers.

Researchers there noted that the clinical picture, which was originally felt to be juvenile rheumatoid arthritis, had occurred in clusters and at a rate 100 times that expected for JRA. It also was clustered in warm-weather months. Dr. Malawista suggested the name Lyme arthritis and he and his team made the eventual linkage with tick bites. In 1982 Dr. Willy Burgdorfer found the bacterium responsible and Yale scientists wnet to work to develop a vaccine.

It was finally licensed in 1998, but a series of events, detailed by Dr. Plotkin in his medical article, led to it being removed from the market four years later. In brief: the CDC's Advisorty Committee on Immunization Practices (ACIP) gave greater emphasis to protective clothing, tick repellants and, in the event of an infection, consistent early diagnosis and antibiotic treatment, than to the vaccine, even for those at high risk. Then it was only tested in adults and more in the group who got the vaccine than in the control group experienced some transient joint soreness...but not actual arthritis (typically red,hot, swollen, painful joints. The marketing of the drug was inappropriately directed at a lay, not a medical audience. A class action suit was brought against Glaxo, the drug company which produced the vaccine and, in spite of later studies showing no increase in Lyme-related joint disease, was settled by Glaxo for $1 million in 2003. Only the lawyers involved got any money.

By then the vaccine was off the market.

It's clearly time for it to come back, perhaps in a new version, perhaps developed by a different company, but, in any case a human Lyme disease vaccine is needed.

In the January 25, 2013 online edition of The New York Times I found a highly significant article titled "F.D.A. Likely to Add Limits on Painkillers." An advisory panel to the Food and Drug administration wants to strengthen the current rules about such drugs as Vicodin, a frequently prescribed powerful pain pill.

Money sometimes blocks the adoption of sensible rules

Similar recommendations failed to make it through Congress last year; they were lobbied against by business interests with considerable heft behind them.

Now Vicodin and other drugs made from hydrocodone aren't the worst problem, but, as you'll see, they are a way to call attention to medications that for the past four years have caused more deaths in the United States than traffic accidents, or those from illegal drugs including heroin and cocaine.

I went back to an article in the Journal of the American Medical Association, AKA JAMA. It was published on Dec 14, 2011 in the section called "Vital Signs," and was a CDC look at overdoses of prescription opioid pain relievers (OPRs) in the US, especially during the 1999-2008 time frame. The news was stark; in 2007 nearly 100 people died from these drugs every day, with death rates that have tripled since 1991.

Between 1999 and 2010 the sales of OPRs quadrupled with enough prescribed to give every single one of us US adults a standard dose of these medications every 4 hours for a month. The health-care cost of abuse of these drugs is staggering, estimated at $72.5 billion a year.

Of the total number of US 2008 deaths from drug overdoses (36,450), OPRs were involved in 14,800 and the years of potential life lost before age 65 was comparable to the figure from motor vehicle accidents. I was startled, but in retrospect not entirely surprised that a study showed 3% of American physicians accounting for 62% of the OPRs prescribed.

Some of those doctors are anesthesiologists, oncologists or other physicians fully trained in pain control and working in highly specialized hospital-associated units. Their use of these medications is appropriately aimed at patients with cancer, those with severe acute injuries and perhaps some others whom almost all of us would agree should have whatever it takes to minimize agonizing pain.

But the new rules, which have to be approved by the FDA and then by the Department of Health and Human Services before they actually take effect, make enormous sense to me: refills forbidden without a new prescription; no fax or phone prescriptions, only written ones; and drug distributors being forced to store OPRs in special vaults.

The Times article today notes the panel was not monolithic in their voting (19 to 10) with some highly skeptical that the suggested changes would do much to alter the current surge of inappropriate or illicit drug use in America. One commented that oxycodone-containing products already are in a more restrictive category.

One of the subject matter experts quoted was Dr. Nathaniel Katz, an anesthesia assistant professor at Tufts University medical school. Katz served as Chair of the FDA's Advisory Committee, Anesthesia, Critical Care, and Addiction Products Division, from 2000 to 2004 and thinks the recommended rule was largely symbolic, giving a message both to doctors and patients. He commented that the OPRs the panel was voting on are a relatively minor player. Katz now devotes much of his time to a clinical research company that's attemting to develop new treatments for pain.

Vicodin and like drugs containing hydrocodone are the most widely prescribed OPRs, but are responsible for a minority of deaths with medications containing oxycodone or methadone, although less commonly given to patients, accounting for two-thirds of the drug overdose deaths.

So the question now is whether the proposed new rules make it over the remaining hurdles.

In September of 2011 Dr. Oz, the Columbia University cardiothoracic surgeon turned TV personality, reported on a problem with apple juice. His show is often on one of the six screens in front of our health club's exercise bikes. I didn't know much about him and routinely read a book on the recumbent bike I ride for an hour, so I paid little attention...then.

His comments applied only to apple juice. He had commissioned an independent lab to check the arsenic level in five brands of juice. They found 10 of the 36 samples had arsenic levels higher than the EPA's drinking water standard of 10 parts per billion (ppb).

The FDA called his publicizing the results of his study "irresponsible and misleading," saying drinking all brands of apple juice is safe. What he hadn't asked the lab to do was to determine if that toxin was in its inorganic form, felt to be dangerous, or in the less dangerous organic form. The FDA said they retested the same batches of juice and found the levels of the more toxic form to be well within safe limits, "almost zero."

Their standard for combined organic and inorganic arsenic is 23 ppb; foods or beverages measuring above that level get retested to determine how much inorganic arsenic is present.

Let's think about that cutoff level; drinking water, to be "safe" used to have less than 50 ppb, more recently 10 ppb has been set as the upper limit. As I've mentioned before, the state of New Jersey now has a standard of 5 ppb.

But in at the end of November, 2011, the website, MedPage Today briefly noted the results of a confirmatory study. Consumer Reports decided to measure both arsenic and lead in apple juice and grape juice. Nine of the 88 samples they had checked exceeded the "safe" limit.

This is supposed to be safe

Then in January, 2012, Consumer Reports.org published their full report online. That article mentioned that 25% of their samples had lead levels over the FDA's bottled-water limit of 5 ppb. And of the 10% of the samples with elevated arsenic amounts, most was the highly toxic inorganic variety.

That report is well worth reading. The Consumers Union group, an advocacy offshoot of Consumer Reports urged that new limits be set for these toxins in juice: 5 ppb for lead and 3 ppb for arsenic. Groundwater contamination with those toxins was implicated in the elevated amounts found in fruit juices. Human activities release three times as much arsenic into our environment as do natural sources

Then in early February two senior members of Congress, one from New Jersey and one from Connecticut, introduced the "Arsenic Prevention and Protection from Lead Exposure in Juice Act of 2012," AKA the "APPLE Juice Act of 2012." If it passes, the FDA would be required to establish standards for arsenic and lead in fruit juices in two years time.

The other issue, of course, is how much juice kids actually drink. The American Academy of Pediatrics recommends no juice until age 6 months, and no more than 6 ounces a day until age six. The reality is over a third of a sample of 555 children, 25% of those age two and under and 45% of kids aged from 3 to 5, exceeded those limits.

We've got a long ways to go, but at least we're hearing about these threats to the health of our kids and grandkids.